In this competing application, we have changed the funding mechanism by which we seek support, from P50 to P60, requiring a strengthening and closer evaluation for achievement of our Outreach efforts. We retain our focus on the etiology of alcoholism, including its course and psychiatric comorbidity, with a particular emphasis on the period of young adulthood, with a major (though not exclusive) emphasis on etiologic mechanisms - whether genetic or environmental - that frequently unfold within the family, whether in terms of (a) the emergence of heavy drinking or alcohol problems in adolescent or young adult offspring, or (b) the environmental risk exposures correlated with parental alcoholism that may interact with offspring genetic vulnerabilities, or (c) consequences of partner alcoholism. Our research continues to be guided by its consideration of (i) behavioral undercontrol, (ii) affect regulation, and (iii) pharmacologic vulnerability as three meta-models (not mutually exclusive) for integrating our research findings. The scientific goals and hypotheses of the Center, and its administrative functions, are closely interconnected. Because of the limited resources of a P60, and the high costs of etiologic research on alcoholism, the success of the Center depends critically upon not only the coordination of the Center-based research projects, but also the coordination of these efforts with a larger R01-supported portfolio (see Introduction, Table A.1). In this coordination the Admin Core and Scientific Resource Core (SRC) play critical roles, with the Pilot Project Core (Pilots) playing an important supporting function, in furthering the career development of our large pool of talented junior faculty investigators, and the Outreach Core providing a new focus for, and expansion of, our Outreach efforts. In the Admin Core (Admin), we present an overview of the conceptual structure of the Center, the research priorities that guide its activities, and the administrative structure designed to meet these scientific needs. We outline the research projects of the Center and their interactions with each other and with our associated R01 portfolio that are facilitated through Admin, as well as the role of Admin in oversight and coordination of the operations of the Science Resource, Pilots and Outreach Cores. During the first 4 Vz years of its history (our original Center received funding in June of 1999, but ran through December 2003), our Center had a more traditional behavioral genetic focus in its approach. We greatly broadened our Center focus at the last competing continuation, reflecting in particular recognition of the rapid advances in discovery of genes associated with differences in alcoholism risk through projects such as COGA. This competing continuation is again being submitted after approximately 3.5 years of funding: we encountered delays in NIAAA funding for the first renewal of our Center, with a funding gap until May 2004. With the first generation of Genomewide Association Studies of Alcoholism (including our own GWAS using 4000 informative individuals identified through Australian Twin Register coordinated gene-mapping studies) in progress, we continue this broadened focus, with Center-supported projects that seek to better characterize some of the varied risk-mechanisms, including developmental processes and gene-environment interactions, that may ultimately lead to differences in alcohol dependence risk. These include (i) a series of alcohol challenge experiments focused on clarifying the acute effects of alcohol on executive functioning, thereby introducing a cognitive neuroscience perspective to our Center's integrative behavioral undercontrol and pharmacologic vulnerability themes (project eight); (ii) a follow-up data collection on our GWAS sample, to obtain more detailed retrospective characterization of certain early environmental exposures (e.g. childhood assaultive trauma such as rape) and more proximal environmental measures that may be important modifiers of effects on the course of alcohol consumption and abuse/dependence, as well as updated assessments of persistence versus desistance of alcohol problems and comorbid conditions, and of quantitative measures of heaviness of consumption, to permit more comprehensive analyses of gene-environment interplay, albeit in retrospective data (project seven); (iii) a continuation and extension of project five, adding a molecular epidemiology component to ongoing prospective studies that have followed samples from early adolescence (Chassin and Bucholz studies, Heath study in part) or late adolescence (Sher and Anokhin studies, Heath study in part) through young adulthood, and with assessments that span the domains of behavioral undercontrol and negative affect, to allow prospective characterization of gene-environment interplay effects on risk; and a narrower focusing of our palm-top computer based project (project six), using Ecological Momentary Assessment (EMA) to investigate alcohol consumption patterns associated with affect-regulation in a patient group characterized by severe affective instability and self-control deficits and increased risks of alcohol dependence, smoking and other substance involvement (borderline patient series) compared to controls (continuation of project six) - using borderline personality disorder, which is characterized by both high negative affect and high impulsivity, as a model system in which to examine the relationship between affect dysregulation, alcohol use, and comorbid smoking behavior. Project four (Children-of-Twins project) will seek R01 funding to continue data-collection; its goals are no longer a good fit with the immediate focus of our Center-based projects: a progress report is included as an appendix. Project three was not funded